Diabetes Mellitus Is a Chronic Disease that Can Benefit from Therapy with Induced Pluripotent Stem Cells

Abstract

Diabetes mellitus (DM) is one of the main causes of morbidity and mortality, with an increasing incidence worldwide. The impact of DM on public health in developing countries has triggered alarm due to the exaggerated costs of the treatment and monitoring of patients with this disease. Considerable efforts have been made to try to prevent the onset and reduce the complications of DM. However, because insulin-producing pancreatic β-cells progressively deteriorate, many people must receive insulin through subcutaneous injection. Additionally, current therapies do not have consistent results regarding the prevention of chronic complications. Leveraging the approval of real-time continuous glucose monitors and sophisticated algorithms that partially automate insulin infusion pumps has improved glycemic control, decreasing the burden of diabetes management. However, these advances are facing physiologic barriers. New findings in molecular and cellular biology have produced an extraordinary advancement in tissue development for the treatment of DM. Obtaining pancreatic β-cells from somatic cells is a great resource that currently exists for patients with DM. Although this therapeutic option has great prospects for patients, some challenges remain for this therapeutic plan to be used clinically. The purpose of this review is to describe the new techniques in cell biology and regenerative medicine as possible treatments for DM. In particular, this review highlights the origin of induced pluripotent cells (iPSCs) and how they have begun to emerge as a regenerative treatment that may mitigate the pathology of this disease.

Keywords: diabetes mellitus; histone modification; iPSC; pancreatic β-cells; regenerative medicine; transcriptional regulation.

Figure 1

Diabetes mellitus is a global problem. A. The estimated number of people aged over 65 y with DM was 111 million in 2019. (1:5 people of this age are predicted to have DM). It is projected that by 2045, the number of people aged over 65 y with DM will reach 276 million. B. An estimated 1.1 million children and adolescents (aged under 20 y) have type 1 DM. Overweight and obesity are increasing the number of children and adolescents with type 2 DM. C. Three in four people living with DM are working age (aged 20–64 y), and this number is expected to increase to 486 million by 2045. IDF, Atlas of Diabetes 2019 [49].

Figure 2

The pancreas has two main functions. As an exocrine organ, it secretes enzymes to digest proteins, carbohydrates and fats. The endocrine component of the pancreas consists of islets of Langerhans that create and release hormones directly into the bloodstream. Pancreatic endocrine cells are clustered into islets of Langerhans, which are composed of different functional cells. The endocrine pancreas consists of 5 main types of secretory cells, alpha cells (α-cells), which express glucagon; beta cells (β-cells), which express insulin; delta cells (δ-cells), which express somatostatin; gamma cells (γ-cells), which express pancreatic polypeptide; and epsilon cells (ε-cells), which express ghrelin. In adults, 60% of islet cells are β-cells, and 30% are α-cells. Different types of endocrine cells establish a paracrine network and interact with peptides involved in an autocrine-mediated hormone secretion. * Enterochormaphin cells have been described in human in vitro β-cells differentiation [91].

Figure 3

Islets obtained from the human or porcine pancreas can be transplanted to subjects with diabetes, following some form of immunosuppression. Human pluripotent stem cells can be differentiated into islet progenitor cells, pure beta cells, or mixed islet cells prior to implantation. Both donor pigs and pluripotent stem cells can be genetically engineered to improve survival, function, and cell safety. Cells can be micro, or macro encapsulated prior to implantation to reduce the requirement for chronic immunosuppression. The cells can also be incorporated into a scaffold to support cell survival and graft recovery. Differentiation Protocol is divided in sequential stages (s): FOXA2, Forkhead boxA2 and SOX17, SRY-box transcription factor 17, stage 1 (s1); HNF4a, Hepatocyte nuclear factor 4 alpha, stage 2 (s2); PDX1, pancreatic and duodenal homeobox 1 and SOX9, SRY-box transcription factor 9, stage 3 (s3); NKX6.1, Nirenberg and Kim homeo box 6.1 and PTFA1, pancreas associated transcription factor 1a, stage 4 (s4); NGN3, Neurogenin 3 and NEUROD1 Neuronal differentiation 1, stage 5 (s5); INS, insulin and MAFA, V-maf musculoaponeurotic fibrosarcoma oncogene homolog A, stage 6 (s6); ESC, embryonic stem cells; iPSC, induced pluripotent stem cells; TF’s: transcription factors; OKSM: octamer-binding transcription factor 4 (Oct4), Krüppel-like factor 4 (Klf4), Sex determining region Y-box2 (Sox2) and oncogene of myelomatosis (c-Myc).

Figure 4

Graphic representation of the influence of the methylation pattern on pancreas development. The development of pancreatic islet cells are subject to a number of epigenetic variations. The modifications of the methylation of histones 3 in lysine residues 9 and 27 (H3K9 and H3K27) stand out. The highest number of genes marked by H3K9me3 is detected at the germ layer stage in endoderm. SET domain bifurcated histone-lysine methyltransferase (STEDb1), Suppressor of Variegation 3-9 Homolog 1, -2 (SUV39H1), -SUV39H2 and the Polycomp complex (PRC2) produce hypermethylation of the lysine residues (H3K9me3 and H3K9me3). After the differentiation of the Endocrine pancreas cells. Progressive loss of H3K9me3 and H3K27me3 at lineage-specific genes mediated by lysine demethylases, KDM4A, -KDM4D, -KDM3A, -KDM6A.